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Papers by Ian Larson

Journal of Pharmaceutical Sciences, 2008

The purpose of this study was to characterise the role of agglomeration on salmeterol xinafoate (... more The purpose of this study was to characterise the role of agglomeration on salmeterol xinafoate (SX) dispersion from mixtures for inhalation by varying the SX concentration and the proportion of fine lactose (FL). SX concentrations and SX:FL ratios ranged from 1.0% to 5.0% (w/w) and from 1:0 to 1:8, respectively. The in vitro deposition of SX was measured using a twin stage impinger (TSI). The aerosol was characterized by particulate capture in the TSI stages and subsequent imaging by scanning electron microscopy and by real-time particle sizing. The presence of coarse lactose reduced SX dispersion compared with SX alone, and the dispersion was independent of SX concentration. SX dispersion in binary mixtures of SX and FL was independent of SX:FL ratio and was similar to that of carrier-based mixtures with high particulate loads. Increased concentrations of SX and proportions of FL in carrier-based mixtures resulted in increased SX dispersion. Agglomerate formation coincided with increased dispersion. The study demonstrated that agglomeration is one of the important factors in SX dispersion from carrier-based mixtures at high particulate loads. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97: 3140–3152, 2008

Dairy Science & Technology, 2010

Our previous work demonstrated that the powder flowability of a cohesive lactose sample can be im... more Our previous work demonstrated that the powder flowability of a cohesive lactose sample can be improved substantially using a dry coating technique. Our study reported here aims to investigate the influence of host particle size on the modification of powder flowability following dry coating process. Four commercial lactose monohydrate powders with different particle sizes were coated by an intensive mechanical process or mixed using a conventional tumbling process, both with magnesium stearate. All four untreated lactose samples showed a relatively poor powder flow. After dry coating, poured and tapped densities of all the lactose samples increased, while Carr indices and Hausner ratios decreased substantially. The angle of repose values were reduced to a notable extent only for particles with a median size larger than about 7 μm after dry coating. Both specific energy (SE) and cohesion values of lactose samples, measured by a powder rheometer system, decreased substantially after coating. In contrast, no apparent changes in powder flow were evident for conventionally mixed batches, except that in the dynamic powder rheometry measurement, a relatively small change in SE was observed. This study demonstrated that for the finer particles examined, cohesive forces were more influential in the powder bed after the surface treatment and resulted in a relatively poor flow. However, for the larger powders studied, the cohesive inter-particle forces could be overcome after this dry coating, whereby satisfactory flow could be obtained. This study indicated that the host particle size was a critical factor in influencing the modification of cohesive powder flowability.

Journal of Pharmaceutical Sciences, 2004

The objective of this study was to determine the influence of lactose carrier size on drug disper... more The objective of this study was to determine the influence of lactose carrier size on drug dispersion of salmeterol xinafoate (SX) from interactive mixtures. SX dispersion was measured by using the fine particle fractions determined by a twin stage impinger attached to a Rotahaler®. The particle size of the lactose carrier in the SX interactive mixtures was varied using a range of commercial inhalation-grade lactoses. In addition, differing size fractions of individual lactose samples were achieved by dry sieving. The dispersion of SX appeared to increase as the particle size of the lactose carrier decreased for the mixtures prepared from different particle size commercial samples of lactose and from different sieve fractions of the same lactose. Fine particles of lactose (<5 μm) associated with the lactose carrier were removed from the carrier surface by a wet decantation process to produce lactose samples with low but similar concentrations of fine lactose particles. The fine particle fractions of SX in mixtures prepared with the decanted lactose decreased significantly (analysis of variance, p < 0.001) and the degree of dispersion became independent of the volume mean diameter of the carriers (analysis of variance, p < 0.05). The dispersion behavior is therefore associated with the presence of fine adhered particles associated with the carriers and the inherent size of the carrier itself has little influence on dispersion. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93: 1030–1038, 2004

Journal of Pharmaceutical Sciences, 2009

The in vitro dispersion of salmeterol xinafoate (SX) alone and four SX (2.5%)–coarse lactose (CL)... more The in vitro dispersion of salmeterol xinafoate (SX) alone and four SX (2.5%)–coarse lactose (CL) mixtures containing 0%, 5%, 10% and 20% micronised lactose (ML) was monitored during 18-month storage at 33%, 55% and 75% relative humidity (RH) using a twin stage impinger. The surface moisture was monitored over 2 months by thermo gravimetric analysis. The morphology was determined by scanning electron microscopy. An aerosizer was used to compare the agglomerate strengths of formulations before and after storage at 75% RH. Upon storage, no significant difference occurred in fine particle fraction (FPF) of any formulation at 33% and 55% RH. Within 8 weeks, the FPF of mixture containing 20% ML (M20F) significantly decreased from 11.3% to 7.7% at 75% RH (p = 0.008) and to 4.9% at 95% RH (p = 0.001). The calculated capillary forces were greater for ML–ML contact than other particle interactions and the propensity of ML–ML contacts was higher in M20F. The agglomerate strength of M20F significantly increased after storage. The study concluded that the critical factors for decreased dispersion of SX formulations were RH of 75% or greater and the presence of high concentrations of ML due to capillary forces and/or solid bridge formation of ML leading to increased agglomerate strength. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:1015–1027, 2009

Pharmaceutical Research, 2006

Purpose The study investigated the role of agglomeration and the effect of fine lactose size on t... more Purpose The study investigated the role of agglomeration and the effect of fine lactose size on the dispersion of salmeterol xinafoate (SX) from SX–lactose mixtures for inhalation. Methods Particle size distributions were characterised by Malvern Mastersizer S, Aerosizer and Spraytec, and imaging conducted by scanning electron microscopy (SEM). Inter-particulate adhesion was quantified by atomic force microscopy. Deposition of SX was measured using a twin stage impinger. SX was analysed using validated high-performance liquid chromatography method (r 2=1.0, CV=0.4–1.0%). Results Addition of fine lactose with a volume median diameter (VMD) of 7.9 μm to a SX–lactose carrier and carrier-free mixture resulted in significantly better dispersion (16.8% for 20% added fine lactose) than fractions with VMD of 3.0, 17.7 and 33.3 μm (less than 9.1% for 20% fine lactose). Using the carrier-free mixtures, particle sizing of the aerosol cloud using the Spraytec, coupled with the application of the Aerosizer using differing dispersion energies and SEMs of the samples, indicated that an open packed, agglomerate structure improved SX dispersion. The highest extent of SX dispersion occurred when SX and fine lactose were detached from the surface, usually in the form of loose agglomerates. Conclusions The outcomes of this research demonstrated how agglomerate structure influenced dispersion and the key role of fine lactose particle size in SX dispersion from mixtures for inhalation.

Journal of Pharmaceutical Sciences, 2005

Adhesion force distributions of silica spheres (5 and 20 µm) and salmeterol xinafoate (4 µm) part... more Adhesion force distributions of silica spheres (5 and 20 µm) and salmeterol xinafoate (4 µm) particles with inhalation grade lactose surfaces and spin coated lactose films were determined by atomic force microscopy (AFM) to investigate the influence of surface roughness on the force distributions. The roughness of lactose particles and films was determined by both AFM and confocal microscopy (CM); the lactose particles showed RMS Rq values between 0.93 and 2.2 µm. The adhesion force distributions for silica and SX probes were significantly different for the different lactose carriers and broad, e.g., the adhesion force distribution between a 5 µm silica sphere and lactose particles ranged from 5 to 105 nN. This contrasted with distributions on smooth spin coated lactose films (RMS Rq of 0.28 nm) which were not significantly different and were narrow, e.g., the adhesion force distribution between a 5 µm silica sphere and spin coated lactose films was between 42 and 68 nN. In addition, no significant difference in adhesion force distribution occurred with silica probe size on the lactose carrier surface. The use of X-ray photoelectron spectroscopic analysis confirmed that the lactose surfaces were free of impurities that might contribute to variation in adhesion. Although the almost atomically flat films showed some adhesion variability, the surface roughness of the lactose particles was a major contributing factor to the broad distributions seen in this study. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:1500–1511, 2005

International Journal of Pharmaceutics, 2010

The aim of this study was to investigate the effect of coating on the aerosolization of three mod... more The aim of this study was to investigate the effect of coating on the aerosolization of three model micronized powders. Three model powder materials (salbutamol sulphate, salmeterol xinafoate, triamcinolone acetonide) were chosen not only for their different chemical properties but also for their different physical properties such as shape and size distribution. Each powder was coated with 5% (w/w) magnesium stearate using two different dry mechanofusion approaches. After mechanofusion, both poured and tapped densities for all three model drug powders significantly increased. There were significant improvements in aerosolization behavior from an inhaler device for all model powders after mechanofusion. Such improvements in aerosolization were attributed to the reduction in agglomerate strength caused by decreasing powder intrinsic cohesion via surface modification. The work also indicated that the effect of the coating was dependant on the initial particle properties.

Powder Technology, 2007

Fluid energy milling and wet sieving were used to produce narrow particle size distributions (PSD... more Fluid energy milling and wet sieving were used to produce narrow particle size distributions (PSD) of fine lactose in the size range size b 40 μm. Fluid energy milling (K-tron Soder, USA) occurred at milling pressures of 552 and 690 kPa and feed rates of 400 to 1600 rpm. Wet sieving used 1-butanol pre-saturated with lactose to classify lactose into fractions of nominally b 5 μm, 5-10 μm, 10-20 μm and 20-45 μm. The sonicator was positioned 3 mm above the surface of the sieve during wet sieving. PSD of the lactose fractions were measured by laser diffraction (Malvern MasterSizer S, Malvern Instrument Ltd., U.K.). Fluid energy milling produced a range of mono-modal distributions of lactose with VMD from 2.9 μm to 41.7 μm. The distributions of milled lactose (VMD of 5.5, 20.2 and 31.1 μm) were broad with spans ranging from 1.6 to 12.4. Wet sieving required the use of sonication to achieve classification. Wet sieving removed fine particles b 5 μm in the milled lactose fractions of 5.5 μm and 20.2 μm and 31.1 μm by 60.2%, 90.6% and 95% respectively after 15 repeat wet sieved cycles giving narrow distributions with spans in the range of 0.9-1.6. DSC and PXRD results for both milled and wet sieved lactose were consistent with those of α-lactose monohydrate and β-lactose was not detected.

International Journal of Pharmaceutics, 2007

The aim of this study was to evaluate coarse and fine sugars as potential alternative excipients ... more The aim of this study was to evaluate coarse and fine sugars as potential alternative excipients in dry powder inhalation formulations and to develop a greater understanding of the key interactions between the particulate species in these mixtures. Interactive mixtures composed of salmeterol xinafoate (SX) and different type of sugars (lactose, glucose, mannitol and sorbitol) were prepared using validated laboratory scale mixing. The sugars and SX were characterised by laser diffraction, scanning electron microscopy, atomic force microscopy and loss on drying method. Deposition of SX was measured using a twin-stage impinger and analysed using validated HPLC method (r(2)=1.0, CV=0.4-1.0%). Good correlation existed between the fine particle fraction (FPF) of SX and both the adhesion force and the moisture content. The addition of 10% fine sugars to produce ternary mixtures (i.e. SX, coarse and fine sugars) generally increased dispersion, with the addition of fine glucose&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;fine mannitol&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;fine lactose&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;fine sorbitol. The dispersion of SX showed a reciprocal relationship with the moisture content of the sugars with glucose showing the greatest and sorbitol showing the lowest extent of SX dispersion. The study clearly demonstrated that strong SX adhesion to coarse sugars reduced the extent of dispersion and that surface detachment of the SX and fine sugar from the coarse sugar carrier was important in the dispersion process.

The Journal of Physical Chemistry, 1995

An atomic force microscope has been used to measure the force of interaction between a Si02 glass... more An atomic force microscope has been used to measure the force of interaction between a Si02 glass sphere (-5 p m diameter) and a Ti02 crystal, in an aqueous medium over the pH range 3-9. The force-separation profiles obtained were compared with DLVO theory, which was found to adequately account for the experimental results up to separations of ca. 2 nm. At distances below this point repulsive interactions in excess of DLVO may be present under certain conditions. To complement the diffuse layer potential results extracted from the force-separation data for dissimilar materials, force-separation interactions were also measured between two Si02 glass spheres. For both sets of surfaces, modeling of the experimental forceseparation curves was best achieved using constant-charge rather than constant-potential boundary conditions.

Powder Technology, 2007

The objective was to develop a suitable laser diffraction particle sizing method for cohesive lac... more The objective was to develop a suitable laser diffraction particle sizing method for cohesive lactose present either as agglomerates or adhered onto coarse lactose carriers. Micronised lactose (ML) was prepared by fluid energy milling. Particle size distributions (PSD) were determined by laser diffraction (Malvern Master Sizer S, U.K.). Ethanol, propan-2-ol, 1-butanol and isooctane were selected as dispersants. Sonication for 5 min caused de-agglomeration of agglomerates initially formed in ethanol, propan-2-ol, and 1-butanol; the volume mean diameter (VMD) of ML in ethanol, propan-2-ol, and 1-butanol was 2.9 μm, 2.8 μm and 2.5 μm, respectively. Coarse lactose (Foremost 95 (F95)) showed a mono-modal distribution in all dispersants with a VMD of 117 μm in propan-2-ol. The robustness of particle sizing of ML in each dispersant was determined over time. Propan-2-ol was the most suitable dispersant for ML, as the PSD (VMD of 2.8 ± 0.3 μm) did not change over a 3 h period. In comparison, for ethanol, VMD of FL was stable only for 30 min, but then increased from 2.9 μm to 9.0 μm after 3 h. The particle size changes over time occurring in ethanol were related to dissolution of fine lactose and possible re-crystallisation with subsequent increased VMD. ML added to coarse lactose and existing as agglomerated particles or as particles adhered to the coarse lactose could be determined with the use of a carefully selected sonication time to minimise coarse lactose comminution.

European Journal of Pharmaceutical Sciences, 2011

The purpose of this study was to understand the behaviour of cohesive powder mixtures of salbutam... more The purpose of this study was to understand the behaviour of cohesive powder mixtures of salbutamol sulphate (SS) and micronized lactose (LH300) at ratios of SS:LH300 of 1:1, 1:2, 1:4 and 1:8 under varying air flow conditions. Aerosolisation of particles less than 5.4μm at air flow rates from 30 to 180 l min(-1) was investigated by determining particle size distributions of the aerosolised particles using laser diffraction and fine particle fractions of SS using the twin stage impinger modified for different air flow rates using a Rotahaler(®). The de-agglomeration data were best fitted by a 3-parameter sigmoidal equation using non-linear least squares regression and characterised by the estimated parameters. De-agglomeration air flow rate profiles showed that SS:LH300 mixtures with increased lactose content (1:4 and 1:8) improved powder aerosolisation, but lactose had negligible effect on SS aerosolisation at the higher and lower limits of air flow rates studied. De-agglomeration flow rate profiles of SS-LH300 mixtures with increased lactose content (1:4 and 1:8) were greater than theoretically expected based on weighted individual SS and LH300 profiles. This indicated that interactions between the cohesive components led to enhanced de-agglomeration. The composition of the aerosol plume changed with air flow rate. This approach to characterising aerosolisation behaviour has significant applications in understanding powder structures and in formulation design for optimal aerosolisation properties.

Pharmaceutical Research, 2004

Purpose. The role of fine lactose in the dispersion of salmeterol xina- foate (SX) from lactose m... more Purpose. The role of fine lactose in the dispersion of salmeterol xina- foate (SX) from lactose mixtures was studied by modifying the fine lactose concentration on the surface of the lactose carriers using wet decantation. Methods. Fine lactose was removed from lactose carriers by wet decantation using ethanol saturated with lactose. Particle sizing was achieved by laser diffraction. Fine particle fractions (FPFs) were determined by Twin Stage Impinger using a 2.5% SX mixture, and SX was analyzed by a validated high-performance liquid chromatography method. Adhesion forces between probes of SX and silica and the lactose surfaces were determined by atomic force microscopy. Results. FPFs of SX were related to fine lactose concentration in the mixture for inhalation grade lactose samples. Reductions in FPF (2- tp 4-fold) of Aeroflo 95 and 65 were observed after removing fine lactose by wet decantation; FPFs reverted to original values after addition of micronized lactose to decanted mixtures. FPFs of SX of sieved and decanted fractions of Aeroflo carriers were significantly different (p < 0.001). The relationship between FPF and fine lactose concentration was linear. Decanted lactose demonstrated surface modification through increased SX-lactose adhesion forces; however, any surface modification other than removal of fine lactose only slightly influenced FPF. Conclusions. Fine lactose played a key and dominating role in controlling FPF. SX to fine lactose ratios influenced dispersion of SX with maximum dispersion occurring as the ratio approached unity.

Langmuir, 1997

An atomic force microscope has been used to study the forces between a silica sphere in the collo... more An atomic force microscope has been used to study the forces between a silica sphere in the colloidal size range and silica or mica flat surfaces as a function of distance of separation. At low ionic strength, independent electrokinetic measurements ( potentials) of both the spheres (by electrophoresis) and flat surfaces (by streaming potential) under the same conditions show excellent agreement with the diffuse double layer potentials derived from the force data using conventional DLVO theory. At higher ionic strength, the electrokinetically derived potentials were found to deviate from those derived from the fitted atomic force microscopy data, and a short range steric type repulsion was observed between the surfaces, the magnitude of which increased with decreasing pH.

Langmuir, 1997

AFM force measurements were carried out between a silica colloid sphere and an alumina flat cryst... more AFM force measurements were carried out between a silica colloid sphere and an alumina flat crystal over a wide pH range and in both 1 × 10 -4 and 1 × 10 -3 M KNO3 aqueous solutions. Microelectrophoresis and streaming potential experiments were performed on the silica colloid sample and the alumina plate, respectively. The potentials measured by the different techniques were in very good agreement. The results clearly indicate that AFM force measurements can be used to accurately determine diffuse layer potentials of metal oxide materials under these solution conditions.

International Journal of Pharmaceutics, 2009

Injectable thermo-activated hydrogels have shown great potential in biomedical applications inclu... more Injectable thermo-activated hydrogels have shown great potential in biomedical applications including use in therapeutic delivery vehicles. In addition to their biocompatibility, the feasibility of these delivery systems is significantly contributed by their ability to gel at physiological conditions and to release entrapped molecules in a sustained manner. In this study, parameters affecting the gelling behavior and the release characteristics of a neutral hydrogel system based on chitosan and an inorganic orthophosphate salt have been investigated. Monobasic and tribasic phosphate salts were not effective in inducing gelation of chitosan solution. However, in the presence of dibasic phosphate salt such as dipotassium hydrogen orthophosphate (DHO), the acidic chitosan solution was neutralized and gelling at temperature and time regulated by varying chitosan and salt concentrations in the formulation. The release rate of the entrapped macromolecules depended on chitosan concentration, DHO concentration, structural conformation and molecular weight of entrapped agents. The relationship between the morphology of the hydrogel and the release profiles are discussed. Chitosan/DHO (Chi/DHO) hydrogels were found to be cytocompatible as evaluated in an in vitro study using a human cell line. These results indicate the potential of Chi/DHO hydrogels as delivery systems for different therapeutic agents with controlled release kinetics.

Biomaterials, 2009

The current management of primary osteosarcoma (OS) and its secondary metastasis is limited by th... more The current management of primary osteosarcoma (OS) and its secondary metastasis is limited by the lack of an efficient drug delivery system. Here we report an in situ gelling chitosan/dipotassium orthophosphate hydrogel system designed to directly deliver the frontline chemotherapeutic agent (Doxorubicin) in a sustained time period to tumor sites. A significant reduction of both primary and secondary OS in a clinically relevant orthotopic model was measured when doxorubicin was administered with the hydrogel. This hydrogel delivery system also reduced cardiac and dermal toxicity of Doxorubicin in mice. The results obtained from this study demonstrate the potential application of a biodegradable hydrogel technology as an anti-cancer drug delivery system for successful chemotherapy.

Langmuir, 1997

Using an atomic force microscope, the adsorption of 4-(dimethylamino)pyridine and pyridine, in aq... more Using an atomic force microscope, the adsorption of 4-(dimethylamino)pyridine and pyridine, in aqueous solution, onto trisodium citrate equilibrated gold has been monitored by the decrease in the electrostatic potential of the gold surface with time. Pronounced changes in the force-separation curves as a function of time were observed, with determined potential decreases in the range of 20-30 mV. The time dependent diffuse layer potentials changes have been attributed to the displacement of citrate ions on the gold surface by the more strongly adsorbing aromatic amines. citrate adsorbed + amine aqueous h amine adsorbed + citrate aqueous

Journal of The American Chemical Society, 1993

An atomic force microscope (AFM) has been used to measure the force of interaction between a ruti... more An atomic force microscope (AFM) has been used to measure the force of interaction between a rutile titanium dioxide colloid and a single macroscopic rutile crystal in aqueous solution. The effect of pH and electrolyte concentration on the force has been investigated. {potentials were derived from electrophoretic mobility measurements on the rutile colloid as a function of pH and electrolyte concentration. Experimental decay lengths for the repulsive electrical double layer interaction are in good agreement with the theoretical Debye lengths at < 1 t 2 M electrolyte. Measurements at the isoelectric point, i.e. pH = 5.6 of the Ti02, could be fitted with a nonretarded Hamaker constant of 6 f 2 J. This value agrees well with the van der Waals interaction calculated within the framework of the Lifshitz theory. In the calculation we used the Ninham-Parsegian representation for the dielectric susceptibility function and have utilized refractive index versus wavelength data to characterize the van der Waals interaction in rutile systems. A non-retarded Hamaker constant of 7 k 1 X 1 C 2 0 J was calculated for two rutile surfaces interacting across water.

Pure and Applied Chemistry, 2005

Republication or reproduction of this report or its storage and/or dissemination by electronic me... more Republication or reproduction of this report or its storage and/or dissemination by electronic means is permitted without the need for formal IUPAC permission on condition that an acknowledgment, with full reference to the source, along with use of the copyright symbol ©, the name IUPAC, and the year of publication, are prominently visible. Publication of a translation into another language is subject to the additional condition of prior approval from the relevant IUPAC National Adhering Organization.

Journal of Pharmaceutical Sciences, 2008

The purpose of this study was to characterise the role of agglomeration on salmeterol xinafoate (... more The purpose of this study was to characterise the role of agglomeration on salmeterol xinafoate (SX) dispersion from mixtures for inhalation by varying the SX concentration and the proportion of fine lactose (FL). SX concentrations and SX:FL ratios ranged from 1.0% to 5.0% (w/w) and from 1:0 to 1:8, respectively. The in vitro deposition of SX was measured using a twin stage impinger (TSI). The aerosol was characterized by particulate capture in the TSI stages and subsequent imaging by scanning electron microscopy and by real-time particle sizing. The presence of coarse lactose reduced SX dispersion compared with SX alone, and the dispersion was independent of SX concentration. SX dispersion in binary mixtures of SX and FL was independent of SX:FL ratio and was similar to that of carrier-based mixtures with high particulate loads. Increased concentrations of SX and proportions of FL in carrier-based mixtures resulted in increased SX dispersion. Agglomerate formation coincided with increased dispersion. The study demonstrated that agglomeration is one of the important factors in SX dispersion from carrier-based mixtures at high particulate loads. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97: 3140–3152, 2008

Dairy Science & Technology, 2010

Our previous work demonstrated that the powder flowability of a cohesive lactose sample can be im... more Our previous work demonstrated that the powder flowability of a cohesive lactose sample can be improved substantially using a dry coating technique. Our study reported here aims to investigate the influence of host particle size on the modification of powder flowability following dry coating process. Four commercial lactose monohydrate powders with different particle sizes were coated by an intensive mechanical process or mixed using a conventional tumbling process, both with magnesium stearate. All four untreated lactose samples showed a relatively poor powder flow. After dry coating, poured and tapped densities of all the lactose samples increased, while Carr indices and Hausner ratios decreased substantially. The angle of repose values were reduced to a notable extent only for particles with a median size larger than about 7 μm after dry coating. Both specific energy (SE) and cohesion values of lactose samples, measured by a powder rheometer system, decreased substantially after coating. In contrast, no apparent changes in powder flow were evident for conventionally mixed batches, except that in the dynamic powder rheometry measurement, a relatively small change in SE was observed. This study demonstrated that for the finer particles examined, cohesive forces were more influential in the powder bed after the surface treatment and resulted in a relatively poor flow. However, for the larger powders studied, the cohesive inter-particle forces could be overcome after this dry coating, whereby satisfactory flow could be obtained. This study indicated that the host particle size was a critical factor in influencing the modification of cohesive powder flowability.

Journal of Pharmaceutical Sciences, 2004

The objective of this study was to determine the influence of lactose carrier size on drug disper... more The objective of this study was to determine the influence of lactose carrier size on drug dispersion of salmeterol xinafoate (SX) from interactive mixtures. SX dispersion was measured by using the fine particle fractions determined by a twin stage impinger attached to a Rotahaler®. The particle size of the lactose carrier in the SX interactive mixtures was varied using a range of commercial inhalation-grade lactoses. In addition, differing size fractions of individual lactose samples were achieved by dry sieving. The dispersion of SX appeared to increase as the particle size of the lactose carrier decreased for the mixtures prepared from different particle size commercial samples of lactose and from different sieve fractions of the same lactose. Fine particles of lactose (<5 μm) associated with the lactose carrier were removed from the carrier surface by a wet decantation process to produce lactose samples with low but similar concentrations of fine lactose particles. The fine particle fractions of SX in mixtures prepared with the decanted lactose decreased significantly (analysis of variance, p < 0.001) and the degree of dispersion became independent of the volume mean diameter of the carriers (analysis of variance, p < 0.05). The dispersion behavior is therefore associated with the presence of fine adhered particles associated with the carriers and the inherent size of the carrier itself has little influence on dispersion. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93: 1030–1038, 2004

Journal of Pharmaceutical Sciences, 2009

The in vitro dispersion of salmeterol xinafoate (SX) alone and four SX (2.5%)–coarse lactose (CL)... more The in vitro dispersion of salmeterol xinafoate (SX) alone and four SX (2.5%)–coarse lactose (CL) mixtures containing 0%, 5%, 10% and 20% micronised lactose (ML) was monitored during 18-month storage at 33%, 55% and 75% relative humidity (RH) using a twin stage impinger. The surface moisture was monitored over 2 months by thermo gravimetric analysis. The morphology was determined by scanning electron microscopy. An aerosizer was used to compare the agglomerate strengths of formulations before and after storage at 75% RH. Upon storage, no significant difference occurred in fine particle fraction (FPF) of any formulation at 33% and 55% RH. Within 8 weeks, the FPF of mixture containing 20% ML (M20F) significantly decreased from 11.3% to 7.7% at 75% RH (p = 0.008) and to 4.9% at 95% RH (p = 0.001). The calculated capillary forces were greater for ML–ML contact than other particle interactions and the propensity of ML–ML contacts was higher in M20F. The agglomerate strength of M20F significantly increased after storage. The study concluded that the critical factors for decreased dispersion of SX formulations were RH of 75% or greater and the presence of high concentrations of ML due to capillary forces and/or solid bridge formation of ML leading to increased agglomerate strength. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:1015–1027, 2009

Pharmaceutical Research, 2006

Purpose The study investigated the role of agglomeration and the effect of fine lactose size on t... more Purpose The study investigated the role of agglomeration and the effect of fine lactose size on the dispersion of salmeterol xinafoate (SX) from SX–lactose mixtures for inhalation. Methods Particle size distributions were characterised by Malvern Mastersizer S, Aerosizer and Spraytec, and imaging conducted by scanning electron microscopy (SEM). Inter-particulate adhesion was quantified by atomic force microscopy. Deposition of SX was measured using a twin stage impinger. SX was analysed using validated high-performance liquid chromatography method (r 2=1.0, CV=0.4–1.0%). Results Addition of fine lactose with a volume median diameter (VMD) of 7.9 μm to a SX–lactose carrier and carrier-free mixture resulted in significantly better dispersion (16.8% for 20% added fine lactose) than fractions with VMD of 3.0, 17.7 and 33.3 μm (less than 9.1% for 20% fine lactose). Using the carrier-free mixtures, particle sizing of the aerosol cloud using the Spraytec, coupled with the application of the Aerosizer using differing dispersion energies and SEMs of the samples, indicated that an open packed, agglomerate structure improved SX dispersion. The highest extent of SX dispersion occurred when SX and fine lactose were detached from the surface, usually in the form of loose agglomerates. Conclusions The outcomes of this research demonstrated how agglomerate structure influenced dispersion and the key role of fine lactose particle size in SX dispersion from mixtures for inhalation.

Journal of Pharmaceutical Sciences, 2005

Adhesion force distributions of silica spheres (5 and 20 µm) and salmeterol xinafoate (4 µm) part... more Adhesion force distributions of silica spheres (5 and 20 µm) and salmeterol xinafoate (4 µm) particles with inhalation grade lactose surfaces and spin coated lactose films were determined by atomic force microscopy (AFM) to investigate the influence of surface roughness on the force distributions. The roughness of lactose particles and films was determined by both AFM and confocal microscopy (CM); the lactose particles showed RMS Rq values between 0.93 and 2.2 µm. The adhesion force distributions for silica and SX probes were significantly different for the different lactose carriers and broad, e.g., the adhesion force distribution between a 5 µm silica sphere and lactose particles ranged from 5 to 105 nN. This contrasted with distributions on smooth spin coated lactose films (RMS Rq of 0.28 nm) which were not significantly different and were narrow, e.g., the adhesion force distribution between a 5 µm silica sphere and spin coated lactose films was between 42 and 68 nN. In addition, no significant difference in adhesion force distribution occurred with silica probe size on the lactose carrier surface. The use of X-ray photoelectron spectroscopic analysis confirmed that the lactose surfaces were free of impurities that might contribute to variation in adhesion. Although the almost atomically flat films showed some adhesion variability, the surface roughness of the lactose particles was a major contributing factor to the broad distributions seen in this study. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:1500–1511, 2005

International Journal of Pharmaceutics, 2010

The aim of this study was to investigate the effect of coating on the aerosolization of three mod... more The aim of this study was to investigate the effect of coating on the aerosolization of three model micronized powders. Three model powder materials (salbutamol sulphate, salmeterol xinafoate, triamcinolone acetonide) were chosen not only for their different chemical properties but also for their different physical properties such as shape and size distribution. Each powder was coated with 5% (w/w) magnesium stearate using two different dry mechanofusion approaches. After mechanofusion, both poured and tapped densities for all three model drug powders significantly increased. There were significant improvements in aerosolization behavior from an inhaler device for all model powders after mechanofusion. Such improvements in aerosolization were attributed to the reduction in agglomerate strength caused by decreasing powder intrinsic cohesion via surface modification. The work also indicated that the effect of the coating was dependant on the initial particle properties.

Powder Technology, 2007

Fluid energy milling and wet sieving were used to produce narrow particle size distributions (PSD... more Fluid energy milling and wet sieving were used to produce narrow particle size distributions (PSD) of fine lactose in the size range size b 40 μm. Fluid energy milling (K-tron Soder, USA) occurred at milling pressures of 552 and 690 kPa and feed rates of 400 to 1600 rpm. Wet sieving used 1-butanol pre-saturated with lactose to classify lactose into fractions of nominally b 5 μm, 5-10 μm, 10-20 μm and 20-45 μm. The sonicator was positioned 3 mm above the surface of the sieve during wet sieving. PSD of the lactose fractions were measured by laser diffraction (Malvern MasterSizer S, Malvern Instrument Ltd., U.K.). Fluid energy milling produced a range of mono-modal distributions of lactose with VMD from 2.9 μm to 41.7 μm. The distributions of milled lactose (VMD of 5.5, 20.2 and 31.1 μm) were broad with spans ranging from 1.6 to 12.4. Wet sieving required the use of sonication to achieve classification. Wet sieving removed fine particles b 5 μm in the milled lactose fractions of 5.5 μm and 20.2 μm and 31.1 μm by 60.2%, 90.6% and 95% respectively after 15 repeat wet sieved cycles giving narrow distributions with spans in the range of 0.9-1.6. DSC and PXRD results for both milled and wet sieved lactose were consistent with those of α-lactose monohydrate and β-lactose was not detected.

International Journal of Pharmaceutics, 2007

The aim of this study was to evaluate coarse and fine sugars as potential alternative excipients ... more The aim of this study was to evaluate coarse and fine sugars as potential alternative excipients in dry powder inhalation formulations and to develop a greater understanding of the key interactions between the particulate species in these mixtures. Interactive mixtures composed of salmeterol xinafoate (SX) and different type of sugars (lactose, glucose, mannitol and sorbitol) were prepared using validated laboratory scale mixing. The sugars and SX were characterised by laser diffraction, scanning electron microscopy, atomic force microscopy and loss on drying method. Deposition of SX was measured using a twin-stage impinger and analysed using validated HPLC method (r(2)=1.0, CV=0.4-1.0%). Good correlation existed between the fine particle fraction (FPF) of SX and both the adhesion force and the moisture content. The addition of 10% fine sugars to produce ternary mixtures (i.e. SX, coarse and fine sugars) generally increased dispersion, with the addition of fine glucose&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;fine mannitol&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;fine lactose&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;fine sorbitol. The dispersion of SX showed a reciprocal relationship with the moisture content of the sugars with glucose showing the greatest and sorbitol showing the lowest extent of SX dispersion. The study clearly demonstrated that strong SX adhesion to coarse sugars reduced the extent of dispersion and that surface detachment of the SX and fine sugar from the coarse sugar carrier was important in the dispersion process.

The Journal of Physical Chemistry, 1995

An atomic force microscope has been used to measure the force of interaction between a Si02 glass... more An atomic force microscope has been used to measure the force of interaction between a Si02 glass sphere (-5 p m diameter) and a Ti02 crystal, in an aqueous medium over the pH range 3-9. The force-separation profiles obtained were compared with DLVO theory, which was found to adequately account for the experimental results up to separations of ca. 2 nm. At distances below this point repulsive interactions in excess of DLVO may be present under certain conditions. To complement the diffuse layer potential results extracted from the force-separation data for dissimilar materials, force-separation interactions were also measured between two Si02 glass spheres. For both sets of surfaces, modeling of the experimental forceseparation curves was best achieved using constant-charge rather than constant-potential boundary conditions.

Powder Technology, 2007

The objective was to develop a suitable laser diffraction particle sizing method for cohesive lac... more The objective was to develop a suitable laser diffraction particle sizing method for cohesive lactose present either as agglomerates or adhered onto coarse lactose carriers. Micronised lactose (ML) was prepared by fluid energy milling. Particle size distributions (PSD) were determined by laser diffraction (Malvern Master Sizer S, U.K.). Ethanol, propan-2-ol, 1-butanol and isooctane were selected as dispersants. Sonication for 5 min caused de-agglomeration of agglomerates initially formed in ethanol, propan-2-ol, and 1-butanol; the volume mean diameter (VMD) of ML in ethanol, propan-2-ol, and 1-butanol was 2.9 μm, 2.8 μm and 2.5 μm, respectively. Coarse lactose (Foremost 95 (F95)) showed a mono-modal distribution in all dispersants with a VMD of 117 μm in propan-2-ol. The robustness of particle sizing of ML in each dispersant was determined over time. Propan-2-ol was the most suitable dispersant for ML, as the PSD (VMD of 2.8 ± 0.3 μm) did not change over a 3 h period. In comparison, for ethanol, VMD of FL was stable only for 30 min, but then increased from 2.9 μm to 9.0 μm after 3 h. The particle size changes over time occurring in ethanol were related to dissolution of fine lactose and possible re-crystallisation with subsequent increased VMD. ML added to coarse lactose and existing as agglomerated particles or as particles adhered to the coarse lactose could be determined with the use of a carefully selected sonication time to minimise coarse lactose comminution.

European Journal of Pharmaceutical Sciences, 2011

The purpose of this study was to understand the behaviour of cohesive powder mixtures of salbutam... more The purpose of this study was to understand the behaviour of cohesive powder mixtures of salbutamol sulphate (SS) and micronized lactose (LH300) at ratios of SS:LH300 of 1:1, 1:2, 1:4 and 1:8 under varying air flow conditions. Aerosolisation of particles less than 5.4μm at air flow rates from 30 to 180 l min(-1) was investigated by determining particle size distributions of the aerosolised particles using laser diffraction and fine particle fractions of SS using the twin stage impinger modified for different air flow rates using a Rotahaler(®). The de-agglomeration data were best fitted by a 3-parameter sigmoidal equation using non-linear least squares regression and characterised by the estimated parameters. De-agglomeration air flow rate profiles showed that SS:LH300 mixtures with increased lactose content (1:4 and 1:8) improved powder aerosolisation, but lactose had negligible effect on SS aerosolisation at the higher and lower limits of air flow rates studied. De-agglomeration flow rate profiles of SS-LH300 mixtures with increased lactose content (1:4 and 1:8) were greater than theoretically expected based on weighted individual SS and LH300 profiles. This indicated that interactions between the cohesive components led to enhanced de-agglomeration. The composition of the aerosol plume changed with air flow rate. This approach to characterising aerosolisation behaviour has significant applications in understanding powder structures and in formulation design for optimal aerosolisation properties.

Pharmaceutical Research, 2004

Purpose. The role of fine lactose in the dispersion of salmeterol xina- foate (SX) from lactose m... more Purpose. The role of fine lactose in the dispersion of salmeterol xina- foate (SX) from lactose mixtures was studied by modifying the fine lactose concentration on the surface of the lactose carriers using wet decantation. Methods. Fine lactose was removed from lactose carriers by wet decantation using ethanol saturated with lactose. Particle sizing was achieved by laser diffraction. Fine particle fractions (FPFs) were determined by Twin Stage Impinger using a 2.5% SX mixture, and SX was analyzed by a validated high-performance liquid chromatography method. Adhesion forces between probes of SX and silica and the lactose surfaces were determined by atomic force microscopy. Results. FPFs of SX were related to fine lactose concentration in the mixture for inhalation grade lactose samples. Reductions in FPF (2- tp 4-fold) of Aeroflo 95 and 65 were observed after removing fine lactose by wet decantation; FPFs reverted to original values after addition of micronized lactose to decanted mixtures. FPFs of SX of sieved and decanted fractions of Aeroflo carriers were significantly different (p < 0.001). The relationship between FPF and fine lactose concentration was linear. Decanted lactose demonstrated surface modification through increased SX-lactose adhesion forces; however, any surface modification other than removal of fine lactose only slightly influenced FPF. Conclusions. Fine lactose played a key and dominating role in controlling FPF. SX to fine lactose ratios influenced dispersion of SX with maximum dispersion occurring as the ratio approached unity.

Langmuir, 1997

An atomic force microscope has been used to study the forces between a silica sphere in the collo... more An atomic force microscope has been used to study the forces between a silica sphere in the colloidal size range and silica or mica flat surfaces as a function of distance of separation. At low ionic strength, independent electrokinetic measurements ( potentials) of both the spheres (by electrophoresis) and flat surfaces (by streaming potential) under the same conditions show excellent agreement with the diffuse double layer potentials derived from the force data using conventional DLVO theory. At higher ionic strength, the electrokinetically derived potentials were found to deviate from those derived from the fitted atomic force microscopy data, and a short range steric type repulsion was observed between the surfaces, the magnitude of which increased with decreasing pH.

Langmuir, 1997

AFM force measurements were carried out between a silica colloid sphere and an alumina flat cryst... more AFM force measurements were carried out between a silica colloid sphere and an alumina flat crystal over a wide pH range and in both 1 × 10 -4 and 1 × 10 -3 M KNO3 aqueous solutions. Microelectrophoresis and streaming potential experiments were performed on the silica colloid sample and the alumina plate, respectively. The potentials measured by the different techniques were in very good agreement. The results clearly indicate that AFM force measurements can be used to accurately determine diffuse layer potentials of metal oxide materials under these solution conditions.

International Journal of Pharmaceutics, 2009

Injectable thermo-activated hydrogels have shown great potential in biomedical applications inclu... more Injectable thermo-activated hydrogels have shown great potential in biomedical applications including use in therapeutic delivery vehicles. In addition to their biocompatibility, the feasibility of these delivery systems is significantly contributed by their ability to gel at physiological conditions and to release entrapped molecules in a sustained manner. In this study, parameters affecting the gelling behavior and the release characteristics of a neutral hydrogel system based on chitosan and an inorganic orthophosphate salt have been investigated. Monobasic and tribasic phosphate salts were not effective in inducing gelation of chitosan solution. However, in the presence of dibasic phosphate salt such as dipotassium hydrogen orthophosphate (DHO), the acidic chitosan solution was neutralized and gelling at temperature and time regulated by varying chitosan and salt concentrations in the formulation. The release rate of the entrapped macromolecules depended on chitosan concentration, DHO concentration, structural conformation and molecular weight of entrapped agents. The relationship between the morphology of the hydrogel and the release profiles are discussed. Chitosan/DHO (Chi/DHO) hydrogels were found to be cytocompatible as evaluated in an in vitro study using a human cell line. These results indicate the potential of Chi/DHO hydrogels as delivery systems for different therapeutic agents with controlled release kinetics.

Biomaterials, 2009

The current management of primary osteosarcoma (OS) and its secondary metastasis is limited by th... more The current management of primary osteosarcoma (OS) and its secondary metastasis is limited by the lack of an efficient drug delivery system. Here we report an in situ gelling chitosan/dipotassium orthophosphate hydrogel system designed to directly deliver the frontline chemotherapeutic agent (Doxorubicin) in a sustained time period to tumor sites. A significant reduction of both primary and secondary OS in a clinically relevant orthotopic model was measured when doxorubicin was administered with the hydrogel. This hydrogel delivery system also reduced cardiac and dermal toxicity of Doxorubicin in mice. The results obtained from this study demonstrate the potential application of a biodegradable hydrogel technology as an anti-cancer drug delivery system for successful chemotherapy.

Langmuir, 1997

Using an atomic force microscope, the adsorption of 4-(dimethylamino)pyridine and pyridine, in aq... more Using an atomic force microscope, the adsorption of 4-(dimethylamino)pyridine and pyridine, in aqueous solution, onto trisodium citrate equilibrated gold has been monitored by the decrease in the electrostatic potential of the gold surface with time. Pronounced changes in the force-separation curves as a function of time were observed, with determined potential decreases in the range of 20-30 mV. The time dependent diffuse layer potentials changes have been attributed to the displacement of citrate ions on the gold surface by the more strongly adsorbing aromatic amines. citrate adsorbed + amine aqueous h amine adsorbed + citrate aqueous

Journal of The American Chemical Society, 1993

An atomic force microscope (AFM) has been used to measure the force of interaction between a ruti... more An atomic force microscope (AFM) has been used to measure the force of interaction between a rutile titanium dioxide colloid and a single macroscopic rutile crystal in aqueous solution. The effect of pH and electrolyte concentration on the force has been investigated. {potentials were derived from electrophoretic mobility measurements on the rutile colloid as a function of pH and electrolyte concentration. Experimental decay lengths for the repulsive electrical double layer interaction are in good agreement with the theoretical Debye lengths at < 1 t 2 M electrolyte. Measurements at the isoelectric point, i.e. pH = 5.6 of the Ti02, could be fitted with a nonretarded Hamaker constant of 6 f 2 J. This value agrees well with the van der Waals interaction calculated within the framework of the Lifshitz theory. In the calculation we used the Ninham-Parsegian representation for the dielectric susceptibility function and have utilized refractive index versus wavelength data to characterize the van der Waals interaction in rutile systems. A non-retarded Hamaker constant of 7 k 1 X 1 C 2 0 J was calculated for two rutile surfaces interacting across water.

Pure and Applied Chemistry, 2005

Republication or reproduction of this report or its storage and/or dissemination by electronic me... more Republication or reproduction of this report or its storage and/or dissemination by electronic means is permitted without the need for formal IUPAC permission on condition that an acknowledgment, with full reference to the source, along with use of the copyright symbol ©, the name IUPAC, and the year of publication, are prominently visible. Publication of a translation into another language is subject to the additional condition of prior approval from the relevant IUPAC National Adhering Organization.